Long-term follow up of prostate cancer patients treated with radiation therapy (RT) reveals that almost half suffer a relapse. Moreover, there is some evidence to support that the regions in the prostate with the greatest tumor burden are the regions that are at highest risk of harboring persistent disease after RT. We propose to use a novel method of high-dose ablative RT delivery to the tumor volume identified by imaging studies. Multiparameter MRI, and in particular Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) is very promising for the in vivo 3D localization of the tumor area. We have developed a novel approach for analysis of DCE-MRI based on an unsupervised pattern recognition technique. Our preliminary data suggest that the technique is sensitive in detecting the presence/absence of tumor and its results can be directly translated to the RT planning system for tailored radiation dose delivery. The RT technique, deemed Lattice Extreme Ablative Dose (LEAD) RT, involves the creation of high doses shaped in cylinders through the DCE- MRI defined region(s) and adjacent apparently normal prostate in a lattice framework. We propose a single- arm phase I clinical trial for LEAD RT delivery in a single fraction of 12-14 Gy prior to standard fractions (2.0 Gy per day) for an additional 76 Gy. The hypothesized benefits of the approach are induction of tumor endothelial cell death and possibly bystander effects including reduced tumor interstitial fluid pressure in densely populated tumors due to rapid cell kill. We also hypothesize that the resulting improved oxygenation of the tumor tissue will enhance the effect of the standard external beam RT component. By using dose cylinders with small diameters (6-7 mm) and not attempting to cover the full extent of the tumor, normal tissues will be more easily spared. As more men are presenting with prostate cancer at younger ages and are living longer, the need to ensure complete tumor cell eradication after RT, while keeping normal tissue toxicity and complications low is of paramount importance for the clinical management of the disease. In this proposal we also aim to develop an approach for obtaining biomarkers from directed biopsies using DCE-MRI tumor maps fused to real-time transrectal ultrasound images via the ArtemisTM system (Eigen Inc., Grass Valley, California). Biomarkers from biopsies from the index lesion(s) will be compared to those from tumor in other areas of the prostate. We will establish a novel approach to assessing biomarkers in these aggressive areas versus other tumor regions, which will better set the stage for identifying how molecular abnormalities dictate patient outcome during radiotherapy. PUBLIC HEALTH RELEVANCE: We propose to use a novel method for delivery of an ablative radiation dose to define by imaging. tumor area in the prostate. By using concentrated dose cylinders with small diameter normal tissues will be more easily spared while potentially eradicating the tumor cells successfully. We will determine the feasibility and toxicity of the approach in a Phase I clinical trial.